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com
Extended report
c Additional data
(supplementary tables 1–7,
supplementary methods,
supplementary material on
toxicity case reports and
supplementary discussion) are
published online only at http://
ard.bmj.com/content/vol69/
issue1
1
Service of Internal Medicine,
Hospital De Cruces, University
Of The Basque Country, Bizkaia,
Spain; 2 Laboratory Of
Autoimmune Diseases ‘‘Josep
Font’’, IDIBAPS, Hospital Clinic,
Barcelona, Spain; 3 Lupus
Research Unit, The Rayne
Institute, St. Thomas’ Hospital,
King’s College, London, UK
Correspondence to:
G Ruiz-Irastorza, Servicio de
Medicina Interna, Hospital de
Cruces, 48903-Bizkaia, Spain;
r.irastorza@euskalnet.net
Accepted 14 December 2008
Published Online First
22 December 2008
20
Clinical efficacy and side effects of antimalarials in
systemic lupus erythematosus: a systematic review
G Ruiz-Irastorza,1 M Ramos-Casals,2 P Brito-Zeron,2 M A Khamashta3
ABSTRACT
Background: Antimalarial drugs (AMs), chloroquine (CQ)
and hydroxychloroquine (HCQ), are frequently withdrawn
in patients with lupus with either severe or remitting
disease. However, additional effects beyond immuno-
modulation have been recently described. The aim of the
present work was to analyse all the published evidence of
the beneficial and adverse effects of AM therapy in
systemic lupus erythematosus (SLE).
Methods: A systematic review of the English literature
between 1982 and 2007 was conducted using the
MEDLINE and EMBASE databases. Randomised controlled
trials (RCTs) and observational studies were selected.
Case reports were excluded except for toxicity reports.
The GRADE system was used to analyse the quality of the
evidence.
Results: A total of 95 articles were included in the
systematic review. High levels of evidence were found
that AMs prevent lupus flares and increase long-term
survival of patients with SLE; moderate evidence of
protection against irreversible organ damage, thrombosis
and bone mass loss. Toxicity related to AMs is infrequent,
mild and usually reversible, with HCQ having a safer
profile. In pregnant women, high levels of evidence were
found that AMs, particularly HCQ, decrease lupus activity
without harming the baby. By contrast, evidence
supporting an effect on severe lupus activity, lipid levels
and subclinical atherosclerosis was weak. Individual
papers suggest effects in preventing the evolution from
SLE-like to full-blown SLE, influencing vitamin D levels and
protecting patients with lupus against cancer.
Conclusions: Given the broad spectrum of beneficial
effects and the safety profile, HCQ should be given to
most patients with SLE during the whole course of the
disease, irrespective of its severity, and be continued
during pregnancy.
Antimalarial drugs (AMs), mainly chloroquine
(CQ) and hydroxychloroquine (HCQ) are among
the oldest drugs used in rheumatology1 and widely
prescribed to patients with systemic lupus erythe-
matosus (SLE). Current recommendations limit the
indication of AMs to patients with non-major
organ involvement,2 hence, AMs are frequently
discontinued in patients with either severe disease
or longstanding remission.3 As a consequence,
more than 50% of patients in many SLE cohorts
have never been treated with AMs.4–6 However,
AMs have shown a substantial impact on the long-
term course of SLE, which could modify the
indications for treatment. Our aim was to system-
atically review all the available evidence on the
beneficial and side effects of AMs in patients with
SLE.
METHODS
Search strategy and selection criteria
A literature search for papers in English from 1982
to 2007 inclusive was performed using the
MEDLINE and EMBASE databases and by manual
search.
The GRADE system was used to analyse the
quality of the evidence7 (see supplementary table 1
for definitions). The final score for the evidence
available on each item was agreed on by all the
authors.
See also supplementary methods.
RESULTS
The selection process is shown in fig 1.
Effects of AMs on SLE activity
A total of 11 studies were found that included data
on the effect of AMs on lupus activity: 4
randomised controlled trials (RCTs),8–11 4 prospec-
tive12–15 and 2 retrospective16 17 cohort studies, and 1
retrospective analysis of data from the extension of
a RCT18 (table 1). Three of these studies, including
a RCT,11 were carried out in pregnant women with
SLE.11 13 15 Two studies were limited to patients
with lupus nephritis.16 17 Lupus activity was
defined using either accepted activity scales, pre-
defined clinical manifestations or criteria for
remission of lupus nephritis.
Whatever the definition of lupus activity was
used, all the studies consistently found it to be
significantly reduced, over 50% in most studies, in
patients treated with AMs. Severe flares were also
reduced, however with borderline statistical sig-
nificance.8 18 In the two retrospective studies of
patients with lupus nephritis, HCQ was identified
as an adjuvant treatment for achieving remis-
sion.16 17 AMs allowed a significant reduction of
corticosteroid treatment in three studies.9 11 14 One
study found lower blood levels of HCQ among
patients experiencing SLE flares.13
In summary, no major limitations were found
regarding the composition of the study groups,
fulfilling American College of Rheumatology
(ACR) classification criteria and diverse in ethnic
origin and disease severity. Groups of treated and
untreated patients were well balanced, without
major differences in potentially confounding vari-
ables. Two RCTs (one in patients who were
pregnant and one in patients who were non-
pregnant) were double blind.8 11
AMs reduce SLE activity in patients who were
pregnant and patients who were non-pregnant
with a high quality of evidence. The effect on
severe flares and on lupus nephritis was either of
borderline statistical significance or supported by
Ann Rheum Dis 2010;69:20–28. doi:10.1136/ard.2008.101766
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Figure 1 Selection process.
retrospective observational studies only, thus with a low quality
of evidence.
Effects of AMs on lipid profile
Nine studies have analysed the effect of AMs on the lipid
profile19–27 (see supplementary table 2). All the studies were
carried out in prospective cohorts of patients with SLE using a
cross-sectional design and one study25 also analysed the effect of
AMs longitudinally.
All but two studies23 27 found significant differences in serum
levels of lipid parameters in patients who were receiving AMs in
comparison with those who were not (supplementary table 2).
The study by Petri et al26 analysed the largest cohort (264
patients with SLE) and was the only study to confirm the
results by multivariate analysis.
The three studies21 22 25 that specifically analysed the effect of
AMs on the lipid profile in patients taking corticosteroids found
a significant reduction in total cholesterol (TC),22 25 very low
density lipoprotein cholesterol (VLDLc),21 22 low density lipo-
protein cholesterol (LDLc)22 and triglyceride (TG)21 levels and a
significant increase in high density lipoprotein cholesterol
(HDLc) levels21 compared with patients taking corticosteroids
alone.
In addition, one cross-sectional study focused on the
prevalence and risk factors of metabolic syndrome in SLE,28
defined by internationally accepted criteria. A total of 102
patients with SLE were studied, with a prevalence of metabolic
syndrome around 30%, higher than in controls. Current use of
HCQ was similar among patients with or without metabolic
syndrome.
Ann Rheum Dis 2010;69:20–28. doi:10.1136/ard.2008.101766
Extended report
In summary, seven out of nine observational studies found
that the use of AMs had a beneficial effect on serum lipid levels,
including patients taking corticosteroid therapy. The two
studies in which a beneficial effect was not found were
performed in patients from China23 and from Iran.27 Although
it is possible that a racial influence modulates the effect of AMs,
the negative results of two studies adds inconsistency. The
magnitude of the effect was variable, but generally modest. The
quality of evidence supporting a clinically meaningful beneficial
effect of AMs in the lipid profile in patients with SLE is rated as
low.
There are no data supporting any protective effect of AMs on
the development of metabolic syndrome.
Effect of AMs on bone metabolism
Two cross-sectional studies have investigated the effect of HCQ
on bone mineral density (BMD).29 30 Both were performed in
small cohorts of patients with SLE (see supplementary table 3).
The multivariate analyses showed that current/past use of
HCQ was associated with a higher mean BMD of the spine29
and the hip,30 the length of HCQ therapy correlated positively
with the mean BMD of the hip and negatively with osteopenia/
osteoporosis of the spine30 and the cumulative HCQ dose
correlated positively with the BMD of the spine.29
A case-control study by Calvo-Alen et al31 found a lower
exposure time to HCQ in patients with osteonecrosis, although
the difference was not significant in the multivariate model. A
similar study by Prasad et al32 including 130 patients (65 cases
and 65 controls) found no differences in the frequency of
treatment with HCQ at any time between cases and controls.
A cross-sectional study performed in 50 patients (25 with SLE
and 25 with fibromyalgia) found lower levels of 1–25 (OH)2
vitamin D in HCQ users, although the difference was
statistically significant only when patients with SLE and
patients with fibromyalgia were combined.33
In summary, a protective effect of HCQ on the BMD,
especially of the spine, was found with a moderate quality of
evidence.
The evidence supporting a protective effect of HCQ on
osteonecrosis was rated as very low.
Likewise, the influence of AMs on 1–25 (OH)2 vitamin D was
supported by very low quality of evidence.
Effects of AMs on atherosclerosis
Eight studies analysed the effect of AMs on atherosclerosis,34–41
defined as the presence of carotid plaque and/or abnormal
intima/media index by carotid ultrasound (n = 5), of coronary
calcifications by CT scan (n = 1) or by studies of vascular
elasticity (n = 2) (see supplementary table 4). All the studies had
a cross-sectional design within prospective cohorts of patients
with SLE. Only one study was specifically designed to analyse
the effect of treatment with HCQ on atherosclerosis.41 Exposure
to AMs was defined as ‘‘ever prior to the study time’’ in five
studies,36–40 one of them using the continuous variable ‘‘time on
CQ’’.37 The remaining three studies analysed current treatment
with HCQ.34 35 41 Patients with clinically apparent cardiovascu-
lar disease were not excluded from any study.
Five studies did not find any effect of current (n = 1) or past
(n = 4) treatment with AMs on the presence of atherosclero-
sis.34 37–40 One study36 found a borderline protective effect of
previous HCQ and another study showed significantly lower
vascular stiffness in premenopausal SLE women receiving
HCQ.35 Only one small study found increased large artery
21
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Extended report

Table 1 Antimalarials and lupus activity

Age
Reference Study type n AM Race (mean) Follow-up Main outcomes AM effect

Canadian Group, RCT 25 HCQ HCQ NA 45 24 weeks SLE flare (ACR Lower rate of SLE flare: (36% vs 73%, p = 0.02)
19918 manifestations)
22 PL Severe flare Lower rate of severe flare: (4% vs 23%,
p = 0.06)
Prednisone dose No difference in dose of prednisone
Meinao et al, RCT 11 CQ CQ W (61%) 32 12 months SLE flare (SLEDAI) Lower rate of SLE flare: (18% vs 83%, p,0.01)
19969
12 Pl Prednisone dose Higher rate of prednisone reduction: (82% vs
25%. p,0.01)
Williams et al, RCT 40 HCQ HCQ W (44%) 42 48 weeks Painful/swollen joints Lower self-assessed severity of joint pain
199410 (p = 0.02)
31 PL B (42%) Grip strength
Self-assessed score of
severity of joint pain
Tsakonas et al, Retrospective 25 HCQ HCQ NA 45 42 months Time to develop a major Lower rate of major flare: (28% vs 50%,
199818 data of flare p = 0.08)
extended RCT
22 PL
Wozniacka et al, Prospective 25 CQ NA 40.6 3 months Change in SLAM score Higher reduction in SLAM score: (9.47 vs 4.92,
200612 cohort p,0.001)
Costedoat et al, Prospective 120 HCQ NA 36 6 months SLE flare (SLEDAI) Lower HCQ blood levels in patients with flare:
200613 cohort (703 vs 1128, p = 0.006)
Serum levels of HCQ
Kasitanon et al, Retrospective 11 HCQ HCQ B (55%) 29.9 12 months Remission in membranous Higher rate of membranous lupus nephritis
200617 cohort lupus nephritis treated with remission: (64% vs 22%, p = 0.036)
MMF
18 no HCQ
Barber et al, Retrospective 35 HCQ W (85.7%) 32.2 38 months Sustained remission of More patients on sustained remission on HCQ:
200616 cohort lupus nephritis (>3 years) (94% vs 53%, p = 0.01)
Levy et al, 200111 RCT 10 HCQ HCQ W (45%) 29 Pregnancy SLE activity (SLEPDAI) Improvement in SLEPDAI score only in patients
duration during pregnancy on HCQ (p = 0.038)
10 PL Prednisone dose Lower prednisone dose at delivery: (4.5 vs
13.7 mg/day, p,0.05)
Clowse et al, Prospective 56 HCQ HCQ W (61%) NA Pregnancy SLE activity (PEA, SLEDAI) Women stopping HCQ higher lupus activity than
200614 cohort duration during pregnancy those never treated and those taking HCQ:
38 HCQ Prednisone use during Flare rate: 55% vs 36%, vs 30%, p = 0.053
previous to pregnancy Maximum SLEDAI: 6.5 vs 5.2 vs 4.2, p = 0.062
pregnancy SLEDAI .4: 84% vs 52%, vs 62%, p = 0.008
163 no HCQ Maximum prednisone dose: 21 vs 23 vs 16,
p = 0.056
Cortes-Hernandez Prospective 60 CQ NA 28 Pregnancy SLE flares (SLEDAI) during CQ discontinuation increased flares (p = 0.02)
et al, 200215 cohort duration pregnancy
ACR, American College of Rheumatology; AM, antimalarial; B, black; CQ, chloroquine; HCQ, hydroxychloroquine; MMF, mycophenolate mofetil; NA, not available; PEA, Physician’s
Estimate of Activity; PL, placebo; RCT, randomised controlled trial; SLAM, Systemic Lupus Activity Measure; SLE, systemic lupus erythematosus; SLE(P)DAI, SLE (Pregnancy)
Disease Activity Index; W, white.

elasticity and reduced systemic vascular resistance among
patients treated with HCQ, as compared with untreated
patients or those receiving corticosteroids only, respectively.41
Data on the effect of AMs on atherosclerosis, usually
subclinical, are limited by the low consistency, lack of specific
design and lack of quality of the studies. The effect was not
quantified in most cases and the exposure to AMs has been
heterogeneously defined, without taking into account the time
of exposure or a possible dose effect. The quality of evidence is
rated as very low.
Effects of AMs on thrombosis
Eight studies have investigated the effects of AM treatment on
thrombosis (table 2). Of them, 5 were prospective observational
cohort studies,4 6 42–44 1 was a cross-sectional study including 133
patients with anti-phospholipid antibodies, of whom 58 had
SLE,45 1 was a cross-sectional study in which the potential
predictors of symptomatic cardiovascular disease were analysed
in retrospect46 and 1 was a retrospective study focused on the
risk and predictors of thrombosis, comparing 162 patients with
SLE and nephritis with 181 patients with primary glomerulone-
phritis.47 Three studies were designed to specifically analyse the
role of AMs on thrombosis42 44 45; the other five studies focused
on the search for variables potentially related with thrombosis
in lupus.4 6 43 46 47
Exposure to AMs was defined as ‘‘ever treated’’ in five
studies4 6 42 46 47 and ‘‘treated prior to the thrombotic event’’ in
the remaining three.43–45 Only one study analysed the relationship
between AM treatment and thrombosis in a time-dependent
manner.44
Studies using the exposure variable ‘‘HCQ ever’’ showed a
diversity of results: one found an inverse association between
HCQ treatment and a history of thrombosis42; one showed no
effect on the endpoint ‘‘arterial thrombosis’’6; one found a
borderline protective effect on venous but not arterial throm-
bosis4; and one found large differences between patients with
and without a history of cardiovascular disease for the number
of months and the cumulative dose of HCQ (33 vs 56 months

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Extended report

Table 2 Effects of antimalarials on thrombosis

Time-
dependent Main
Reference Type of study n HCQ/CQ Race Age (mean) analysis outcome AM effect

Wallace et al, Observational 92 HCQ ever W (70%) 42 No Thrombosis Patients treated with HCQ had less
198742 cohort thrombosis (p,0.05)
Erkan et al, Cross-sectional 58* HCQ prior to W (80%) NA No Thrombosis Prior treatment with HCQ more frequent
200245 study event in patients without thrombosis
(p,0.001)
H (8%)
B (8%)
C (3%)
Toloza et al, Observational 446 HCQ ever B (45%) 36.5 No Arterial No effect (p.0.05)
20046 cohort thrombosis
H (43%)
W (35%)
Mok et al, 20054 Observational 625 HCQ ever C (41%) 337.5 No Thrombosis Arterial thrombosis: OR 0.99 (95% CI
cohort 0.53 to 1.85)
W (36%) Venous thrombosis: OR 0.73 (95% CI
0.38 to 1.40)
B (22%)
Ho et al, 200543 Observational 442 HCQ prior to B (39%) NA No Thrombosis OR 0.53 (95% CI 0.3 to 0.94)
cohort event
H (30%)
W (30%)
de Leeuw et al, Cross-sectional 72 HCQ ever NA 41 No CV disease Patients with CV disease less time (56
200646 study vs 33 months) and lower cumulative
dose of HCQ (631 vs 244 g),
differences not significant
Ruiz-Irastorza et Observational 232 AM at the time W (99%) 36.2 Yes Thrombosis HR 0.28 (95% CI 0.08 to 0.90)
al, 200644 cohort of event
Mok et al, Retrospective SLE 162 HCQ .3 C 29 (SLE) No Arterial Adjusted HR 2.03 (95% CI 0.74 to
200747 cohort months ever thrombosis 5.60); pooled analysis of patients with
SLE and GN
GN 181 42 (GN)
*This study included 133 patients with anti-phospholipid antibodies, of whom 58 had SLE. The results were obtained for the whole group of patients.
AM, antimalarial; B, black; C, Chinese; CQ, chloroquine; CV, cardiovascular; GN, primary glomerulonephritis; H, Hispanic; HCQ, hydroxychloroquine; HR, hazard ratio; NA, not
available; OR, odds ratio; SLE, systemic lupus erythematosus; W, white.

and 244 vs 631 g, respectively), without reaching the level of
statistical significance.46 The study by Mok et al did not find
HCQ to protect from thrombosis.47 However, patients with SLE
and non-SLE glomerulonephritis were mixed up in the analysis,
HCQ being almost exclusively taken by patients with lupus,
itself a predictor of thrombosis, which results in a major
‘‘confounding by indication’’ bias.
The three studies in which exposure to AMs was considered
prior to the thrombotic event found a significant protective
effect on thrombosis, arterial and venous taken as a whole.43–45
This effect was lost after multivariant analysis in the study by
Ho et al.43 HCQ retained its effect after a bivariate analysis in
the study by Erkan et al.45 The only study analysing the effect of
AMs with a Cox multiple failure time survival analysis showed
that they were protective against thrombosis (hazard ratio (HR)
0.28, 95% CI 0.08 to 0.90), after controlling for other variables
such as history of thrombosis, presence of anti-phospholipid
antibodies and treatment with aspirin.44
In summary, the effect of AMs in preventing thrombotic
events was consistently found in studies taking into account the
exposure previous to the event. A dose effect was suggested by
one study with a small sample size, which prevented the
statistical significance of the results. The magnitude of the effect
is high according to the only study with time-dependent analysis,
however, confidence intervals were wide. Accordingly, the
quality of evidence available on this issue is rated as moderate.
However, there are insufficient data to address whether the
antithrombotic effect is present for arterial and venous events.
Effects of AMs on irreversible organ damage
Two prospective observational cohort studies have investigated
the effect of HCQ on the accrual of irreversible organ damage,
as measured using the Systemic Lupus International
Collaborating Clinics–American College of Rheumatology
Damage Index (SDI)48 (see supplementary table 5).
The first study was performed in a cohort of 151 patients
with lupus from Israel, 93.4% of Jewish origin.49 After a
mean follow-up of 45 months, treatment with HCQ had an
inverse and independent relation with SDI values (p = 0.02).
Additionally, patients treated with HCQ showed a higher
damage-free survival than those untreated (p,0.001). No
estimate of the effect was given by the authors.
The second study was performed in the multiethnic
LUMINA (for ‘‘Lupus in Minorities: Nature vs Nurture’’)
cohort.50 A total of 518 patients were included in the
analysis. The effect of HCQ on SDI was adjusted using the
propensity score, which results in a form of pseudorando-
misation of observational cohort studies.51 HCQ treatment
taken at enrolling the cohort was protective against damage
accrual after adjusting for the propensity score (HR 0.73,
95% CI 0.52 to 1.00). In those patients with no damage at
the time of entering the study, the protective effect was
more marked (propensity score-adjusted HR 0.55, 95% CI
0.34 to 0.87).
In summary, the two studies focused on the relation of AMs
are consistent in finding a protective effect of HCQ. The
protective effect was quantified in only one of the studies, HR

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Extended report
Table 3 Effects of antimalarials on survival
Reference Type of study n HCQ/CQ
Hernandez-Cruz et al, Case-control 152 CQ
200153
Ruiz-Irastorza et al, 200644 Prospective cohort 232 HCQ/CQ
with propensity score
analysis
Alarcon et al, 200752 Case-control with 244 HCQ
propensity score
analysis
AM, antimalarial; B, black; CQ, chloroquine; H, Hispanic; HCQ, hydroxychloroquine; HR, hazard ratio; OR, odds ratio; W, white.
being above 0.5, with wide 95% CIs. Therefore, the quality of
evidence on this issue is rated as moderate.
Effects of AMs on survival
Three studies have analysed the long-term effects of AM use in
the survival of patients with SLE44 52 53 (table 3): one case-control
study (case = deceased patients with SLE with autopsy, one
control per case, matched by age and disease duration),53 one
prospective observational cohort study44 and one nested case-
control study (case = deceased patients, three controls per case
matched for time to event) within a prospective cohort.52
Exposure to AMs was always defined as ‘‘ever treated’’. The
first study used a logistic regression analysis including indexes
for severity and lupus activity, as well as all the variables related
to mortality.53 The propensity score analysis (see above) was
used in the other two studies.44 52
The first study was performed in patients with SLE from
Mexico City, Mexico, selected from the autopsy registers and
hospital databases.53 A total of 76 cases and 76 controls were
included. Data were obtained from chart review. The dose of
CQ was lower in deceased than in living patients (3.6 mg/day vs
39.4 mg/day, p,0.001). However, it was not a significant
predictor in the multiple regression model. This study is severely
limited by the retrospective acquisition of data and the likely
‘‘confounding by indication’’ bias.
The second study was performed in a cohort of 232 patients
from the Basque Country, Spain,44 99% of whom were white. In
all, 83% of deaths took place among patients never treated with
AMs. No patients taking either CQ or HCQ died of
cardiovascular causes. Unadjusted and propensity score-
adjusted HR were similar: 0.13 (95% CI 0.04 to 0.39) and 0.14
(95% CI 0.04 to 0.48), respectively.
The third study was performed within the prospective
LUMINA cohort,52 selecting 244 patients from the 608
participants in the cohort. In this case, patients were almost
equally divided among Hispanics, African–Americans and
Caucasians. All patients treated with AMs took HCQ. Within
the whole cohort, 17% of patients not taking HCQ died during
the follow-up, vs 5% of those treated with HCQ (p,0.001). In
the case-control study, unadjusted and propensity score-
adjusted odds ratios (ORs) were 0.28 (95% CI 0.054 to 0.301)
and 0.319 (95% CI 0.118 to 0.864), respectively.
Given its limitations, the Mexican study can only suggest a
beneficial effect of CQ on survival. The two prospective studies,
both using propensity score analysis, have shown a consistent
protective effect of AMs, with a reduction in mortality higher
24
Race Age (mean) Main outcome AM effect
Mexican 28 Survival Dose of CQ in dead vs alive 3.9 vs
39.4 (p,0.001)
CQ non-significant predictor of
survival in logistic regression
W (99%) 36.2 Survival Adjusted HR 0.14 (95% CI 0.04 to
0.48)
Causes of death No cardiovascular deaths in AM
group vs 7 in the untreated group
H (33%) 35 Survival Adjusted OR 0.319 (95% CI 0.118 to
0.864)
B (38%)
W (29%)
than 50% in both cases. Major biases are unlikely to fully
explain these large differences. Thus, we upgraded the score and
consider the quality of evidence on this issue as high.
Adverse effects of AMs
We found four studies analysing the prevalence of all types of
adverse events (AE) in patients with SLE treated with AMs54–57
(table 4). Two were retrospective studies,56 57 one was a
prospective cohort study55 and one was a small RCT comparing
clofazimine and CQ.54 One study included diseases other than
SLE.57 Patients received HCQ only in one study,56 CQ only in
one study54 and one did not make a difference between HCQ
and CQ users.55 Only 1 study57 has compared the frequency of
AE among HCQ and CQ users in a large series of 940 patients
(including 178 with SLE).
The frequency of AE reported in all the studies has been low,
mainly gastrointestinal and cutaneous, usually mild.54–57 The
only study comparing the toxicity of HCQ and CQ found a
higher frequency of AE in patients receiving CQ in comparison
with those receiving HCQ (28.4% vs 14.7%, p,0.001). Overall,
15% of patients discontinued AMs due to toxicity, patients
receiving HCQ being less likely to discontinue the drug due to
side effects than those taking CQ (adjusted HR 0.62, 95% CI
0.40 to 0.96).
Seven studies have evaluated the frequency of retinal toxicity
in patients treated with AMs57–63 (table 4). Three studies
included diseases other than SLE.57 60 62 63 Four studies included
HCQ users,59–61 63 one CQ users58 and two compared HCQ and
CQ users.57 62
In all, 4 studies,57 58 62 64 including 647 patients treated with
CQ for a mean of .10 years, found that 16 (2.5%) patients were
diagnosed as having definite retinal toxicity, in comparison with
only 2 (0.1%) of 2043 patients taking HCQ for a similar period
included in 6 studies57 59 60 62 63 65 (OR 25.88, 95% CI 6.05 to
232.28, p,0.001). When patients classified as having probable
retinal toxicity were added, there were 17/647 (2.6%) CQ users
and 6/2043 (0.3%) HCQ users with toxicity (OR 9.16, 95% CI
3.42 to 28.47, p,0.001).
Johnson et al61 analysed seven patients taking HCQ for a
mean of 14.2 years with an accumulated dose .1 g. Exhaustive
ophthalmological assessment found fine granularity of the
macular pigment epithelium in two patients with borderline
abnormalities of colour vision in one, classified as a possible case
of early toxicity.
Cardiotoxicity of AMs in patients with SLE has been
evaluated in 2 studies66 67 including 70 patients treated with
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Extended report

Table 4 Toxicity of antimalarials

Age
Reference Type of study (follow-up) n AM (mean time use) (mean) Main outcomes AM toxicity

Costedoat et al, Prospective cohort (1 70 SLE HCQ (7.9 years) 38 Cardiotoxicity (ECG) AVB (0%), minor HCD (4%),
200766 year) myocardiopathy (0%)
Leecharonen et al, Retrospective (13 years) 49 SLE CQ (36 months) NS Standard ophthalmological Corneal deposition 6%,
200758 evaluation (corneal deposition retinopathy 16%
and retinopathy)
Wozniacka et al, Prospective cohort (NS) 28 SLE CQ (7 months) 38 Cardiotoxicity (ECG, 24-h ECG HCD (0%), tendency higher QTc
200667 holter) before and after CQ treatment
(363 ms vs 372 ms, p = 0.09)
Bonanomi et al, Cross-sectional study 20 SLE 34 HCQ 40 Retinal toxicity Retinopathy 6%
200664
14 RA
Bezerra et al, 200554 RCT (clofazimine vs CQ) 33 SLE 17 CQ 34 Adverse events Headache 2 (12%), nausea 2
(6 months) (12%), diarrhoea 3 (18%),
urticaria 2 (12%) and ocular 0
(0%) in patients treated with CQ
Mavrikakis et al, Prospective cohort (15 191 SLE HCQ (at least 1 year) 45 Ophthalmological assessment Retinopathy 0.5%
200359 years) (Snellen best-corrected visual
acuity, Farnsworth D-15 panel
test, Rodenstock central visual
field testing, fundoscopy, full
field electroretinography,
fluorescein angiography)
Wang et al, 199955 Prospective cohort study 224 SLE 156 HCQ/CQ (NS) 34 Adverse events Gastrointestinal 11 (7%),
(NS) myopathy 2 (1.3%), headache 2
(1.3%), retinal toxicity 1 (0,6%),
ototoxicity 1 (0,6%), skin rash 1
(0,6%)
Aviña-Zubieta et al, Retrospective (8 years) 557 RA 541 CQ 47 Comparison of side effects Higher frequency of rash (4.3%
199857 between CQ and HCQ vs 2%, p,0.05), corneal
deposits (7% vs 0.8%,
p,0.001), blurred vision (4% vs
1.3%, p,0.01), myopathy
(1.1% vs 0%, p,0.03) and total
side effects (28.4% vs 14.7%,
p,0.001) in patients receiving
CQ in comparison with those
receiving HCQ
178 SLE 399 HCQ Retinopathy Probable retinopathy in 1/541
CQ (0.18%) and 0/399 HCQ (0%)
128 PA
77 other
Levy et al, 199760 Retrospective NS 1207 HCQ NS Retinal toxicity (reviewed by a Definite toxicity 1/1207 (0.08%)
panel of 5 ophthalmologists)
Probable toxicity 4/1207
(0.33%)
65
Spalton et al, 1993 Retrospective 82 SLE HCQ (39 months) 40 Retinal toxicity Retinopathy 0%
Morand et al, 199256 Retrospective 37 SLE HCQ (28 months) 37 Adverse events Dermatological 1 (3%), ocular 0
(0%), gastrointestinal 0 (0%)
Johnson et al, 198761 Retrospective 7 SLE HCQ with a total dose . 42 Ophthalmological assessment Fine granularity of the macular
1 g (14.2 years) (Snellen chart, Amsler grid pigment epithelium (n = 2)
testing, Ishihara plates,
Farnsworth–Munsell 100 hue
test)
Fine granularity of the macular
pigment epithelium and
borderline abnormalities of
colour vision, classified as signs
of possible early toxicity (n = 1)
Finbloom et al, 198562 Retrospective (15 years) 70 SLE 31 CQ 42 Ocular toxicity 6/31 CQ (19%)
26 RA 66 HCQ 39 0/66 HCQ (0%)
14 Other 13 CQ+HCQ NS
Frenkel et al, 198263 Retrospective (15 years) 100 RA/SLE HCQ (36 months) NS Ocular toxicity Retinal toxicity 0 (0%)
AVB, atrioventricular block; CQ, chloroquine; ECG, electrocardiogram; HCD, heart conduction disorders; HCQ, hydroxychloroquine; NS, not specified; PA, paludism; RA, rheumatoid
arthritis; RCT, randomised controlled trial; SLE, systemic lupus erythematosus.

HCQ and 28 patients treated with CQ, respectively. No cases of
clinically relevant cardiotoxicity were reported.
In addition, we analysed the clinical characteristics of case
reports of AM toxicity68–93 (see supplementary table 6 and
supplementary material on toxicity case reports).
In summary, toxicity associated to AM use was infrequent
and generally mild. Large series are consistent in showing the
lack of serious adverse events, even after prolonged use. Overall,
the frequency of adverse events with CQ was higher to that
with HCQ, although data come only from observational

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Extended report
Table 5 Effects of antimalarials in patients with systemic lupus
erythematosus (SLE) graded according to the quality of evidence7
Quality of evidence AM
High:
Reduction of SLE activity (also in pregnancy) CQ/HCQ
Reduction of mortality CQ/HCQ
Moderate:
Increase in BMD HCQ
Protective effect on thrombotic events CQ/HCQ
Protective effect on irreversible organ damage HCQ
Low:
Reduction of severe flares HCQ
Adjuvant effect for achieving LN remission HCQ
Beneficial effect on serum lipid levels CQ/HCQ
Protective effect on osteonecrosis HCQ
Delaying the evolution to SLE HCQ
Protective effect on cancer CQ/HCQ
Very low:
Reduction of 1–25 (OH)2 vitamin D levels HCQ
Reduction of atherosclerosis CQ/HCQ
AM, antimalarial; BMD, bone mineral density; CQ, chloroquine; HCQ,
hydroxychloroquine; LN, lupus nephritis.
studies. Therefore, evidence supporting the global safety of AMs
(HCQ and CQ) is rated as high. HCQ offers a safer profile than
CQ, with a moderate grade of evidence.
Adverse effects of AMs on the fetus
In all, 10 studies reported on the effects of AMs on children born
to lupus mothers.11 14 94–101 A total of 275 pregnant patients with
SLE received HCQ and 36 received CQ. In addition, 1 study
reported on 21 patients (14 with HCQ and 7 with CQ) who
were diagnosed as having either SLE or RA.97 Five studies
included a control group of pregnant women with SLE who had
not been treated compared with patients who had been
treated.14 94 96 98 99 Monitoring for toxicity on the baby included
examination for malformations and also surveillance of ocular,
auditory and neurological problems arising from birth until
more than 4 years of age, depending on the study (see
supplementary table 7).
All the studies are concordant in showing the absolute safety
of AMs during pregnancy: congenital malformations were not
more frequent than in unexposed children and no cases of
ocular, auditory or neurological toxicity were reported.
Therefore, AMs are safe for the fetus when given to the
pregnant mother, with no cases of fetal malformations (beyond
those normally expected) or toxicity reported among more than
300 children exposed to these drugs. Due to the much higher
number of patients with SLE using HCQ as compared with CQ,
the quality of evidence is rated as high for HCQ and moderate
for CQ.
Miscellanea
A retrospective nested cohort study of 130 patients with SLE
analysed the effect of AMs in delaying the completion of ACR
classification criteria in patients with lupus-like disease.102
Patients taking HCQ delayed the time until diagnosis of full-
blown SLE (1.08 vs 0.29 years, p = 0.018), being less likely to
present with proteinuria (p,0.05), leucopenia (p,0.05) or
lymphopenia (p,0.001).
There was 1 study that investigated the effect of AMs (CQ or
HCQ) on the risk of developing cancer in a prospective cohort of
26
235 patients with SLE.103 In all, 13 patients developed cancer;
2/156 (1.3%) in the AM group vs 11/79 (13%) in the non-AM
group (p,0.001). The adjusted HR of developing cancer in
patients treated with AMs vs patients not treated with AMs
was 0.15 (95% CI 0.2 to 0.99).
Both studies need further confirmation of their results. Thus,
current evidence in both cases is rated as low.
See also supplementary discussion.
DISCUSSION
Taking into account the current evidence analysed and
discussed in this paper (table 5), we recommend the treatment
with AMs, preferably HCQ, of most patients with SLE, starting
as soon as the diagnosis has been made. This treatment could be
maintained long term if toxicity does not ensue, whatever the
subsequent course of lupus (pregnancy included) and the
additional medications needed. Routine ophthalmological con-
trols in patients with SLE could be performed according to the
recommendations of the American College of Ophthalmology,74
although less or more frequent controls could be agreed with the
attending ophthalmologist. These conclusions, as well as the
ideal long-term maintenance dose of HCQ (400 mg/day,
200 mg/day or even less) should be confirmed and defined in
future studies and meta-analyses.
Competing interests: None declared.
Provenance and peer review: Not commissioned; externally peer reviewed.
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Correction

There was an error in a letter published in the November issue of the journal (Berger CT, Recher M,
Steiner U, Hauser TM. A patient’s wish: anakinra in pregnancy. Ann Rheum Dis 2009;68:1794–5). It
states that MR and US contributed equally. It should say that CTB and MR contributed equally.
doi:10.1136/ard.2008.105833corr1

28 Ann Rheum Dis 2010;69:20–28. doi:10.1136/ard.2008.101766

 Downloaded from http://ard.bmj.com/ on February 21, 2016 - Published by group.bmj.com

Clinical efficacy and side effects of

antimalarials in systemic lupus
erythematosus: a systematic review
G Ruiz-Irastorza, M Ramos-Casals, P Brito-Zeron and M A Khamashta

Ann Rheum Dis 2010 69: 20-28 originally published online December 22,
2008
doi: 10.1136/ard.2008.101766

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http://ard.bmj.com/content/69/01/20

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Supplementary Supplementary material can be found at:

Material http://ard.bmj.com/content/suppl/2010/01/29/ard.2008.101766.DC1.ht
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References This article cites 103 articles, 43 of which you can access for free at:
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Topic Articles on similar topics can be found in the following collections

Collections Connective tissue disease (4016)
Immunology (including allergy) (4829)
Systemic lupus erythematosus (538)
Epidemiology (1320)

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